Molecular Targets in Hepatocarcinogenesis and Implications for Therapy

Abstract

Hepatocarcinogenesis comprises of multiple, complex steps that occur after liver injury and usually involve several pathways, including telomere dysfunction, cell cycle, WNT/β-catenin signaling, oxidative stress and mitochondria dysfunction, autophagy, apoptosis, and AKT/mTOR signaling. Following liver injury, gene mutations, accumulation of oxidative stress, and local inflammation lead to cell proliferation, differentiation, apoptosis, and necrosis. The persistence of this vicious cycle in turn leads to further gene mutation and dysregulation of pro- and anti-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-10, IL-12, IL-13, IL-18, and transforming growth factor (TGF)-β, resulting in immune escape by means of the NF-κB and inflammasome signaling pathways. In this review, we summarize studies focusing on the roles of hepatocarcinogenesis and the immune system in liver cancer. In addition, we furnish an overview of recent basic and clinical studies to provide a strong foundation to develop novel anti-carcinogenesis targets for further treatment interventions.

Keywords: NF-κB; hepatocarcinogenesis; inflammasome; liver cancer.

Figure 1

Telomerase reverse transcriptase (TERT) mutation prevalence during HCC progression.

Figure 2

Detailed mechanisms in hepatocarcinogenesis. The exposure to hepatotoxic agents triggers gene mutation and local inflammation via Wnt/β-catenin, NF-κB, signaling, the YAP-HIPPO pathway, and angiogenesis pathways. PA and integrin are also involved in the carcinogenesis process.

Figure 3

The role of immunity in hepatocarcinogenesis. After liver damage, cell dysfunction and death triggers local and systemic immune responses, leading to liver cirrhosis and hepatocarcinogenesis. Chronic liver inflammation causes the dysregulation of pro- and anti-inflammatory cytokines, such as IL-1β, IL-6, IL-10, IL-12, IL-13, IL-18, and TGF-β, which inhibit anti-tumor immune responses. The activation of NF-κB and STAT3 signaling is also involved. NF-κB also correlates with the formation of inflammasome, leading to the release of IL-1β. The dysregulated cytokines inhibit antigen presentation cells, leading to over-expression of Th2 cytokines, and decrease the activity of CD8+ T cells via T regulatory cells, invariant natural killer T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, causing immune escape.